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Hormone Resistant Prostate Cancer

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A slide presentation on Hormone resistant prostate cancer and its management

A slide presentation on Hormone resistant prostate cancer and its management

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  • 1. Chemotherapy in HRPC Department of Medical oncology
  • 2. Definition
    • Hormone resistant prostate cancer
      • A rising PSA despite androgen ablation
      • Manifests
        • Rising PSA
        • Symotomatic Progression
        • Radiological evidence of progression despite the serum testosterone been at castrate levels
      • BUT
  • 3. Defn contd
    • Trials defined (similar)
      • Men with advanced and progressive prostate cancer that had failed to respond to standard hormone therapy. Disease progression is observed despite castrate level of testosterone
      • The definition of disease progression
        • appearance of new lesions
        • an increase in size (generally 25%) of existing lesions
        • an increase in pain
        • reduction in performance status
        • Decrease in weight
        • an increase in PSA levels
      • No trial used a rising PSA level as the sole indicator of disease progression.
  • 4. EAU- defn
    • Castrate serum levels of testosterone (testosterone <50 ng/dl or <1.7 nmol/l)
    • Three consecutive rises of PSA, 1 wk apart, resulting in two 50% increases over the nadir
    • Antiandrogen withdrawal for at least 4 wk for flutamide and for at least 6 wk for bicalutamide
    • PSA progression, despite consecutive hormonal manipulations
    • Progression of osseous lesions: progression or appearance of two or more lesions on bone scan or soft tissue lesions using Response Evaluation Criteria in Solid Tumours and with nodes >2 cm in diameter
  • 5. Why treat?
    • Morbidity
      • QOL
    • Mortality
      • Incurable situation
      • Median life expectancy 12-18 months
    Use of chemo for palliation Of symptoms and for survival benefit
  • 6. Mitoxantrone The major toxicities were associated with mi- toxantrone include grade 3/4 neutropenia (7%), nausea and vomiting, alopecia (24%) and cardiotoxicity (66%).
  • 7. Docetaxol TAX 327
  • 8. Side effects
  • 9. Other studies
  • 10. Lesson learned?
    • In view of the apparent lack of superior activity and greater toxicity by the addition of estramustine, docetaxel every 3 weeks plus low-dose prednisone can be considered as the current standard treatment
    • The optimal duration of docetaxel based chemotherapy for CRPC has not yet been established.
      • Tax 327 10 cycles
      • SWOG 99-16 12 cycles.
    • Standard practice is to treat patients with a fixed number of 10cycles of chemotherapy
  • 11. Prognostic factors
    • TAX 327 four independent risk factors predicted for not reaching a 30% PSA decline in 3-month PSA
      • Significant baseline pain
      • Visceral metastases
      • anaemia (haemoglobin <13g/dl)
      • bone scan progression at baseline
    • low-risk group 0−1 risk factors – Median OS 25.7 m
    • intermediate-risk group 2 risk factors – 18.7 m
    • high-risk group of patients 3−4 risk factors-12.8 months,
  • 12. When to start therapy?
  • 13. PSA DT
  • 14. Response measurement
    • PCWG 2 defined criteria of progression on the basis of changes in PSA, bone metastases, and measurable disease
      • PSA progression has been defined as a 25% or greater increase and an absolute increase of 2ng/mL or more from the lowest documented PSA level,which is confirmed by a second value obtained 3 or more weeks later.
      • When the bone scan is the sole indicatorof progression- when at least two or more new lesions are seen on a bone scan compared with prior scans.
      • Measurable ds- RECIST
    • Surrogate markers- 30% decline in PSA at 3 months and Post treatment PSA velocity
  • 15. Addition in first line
    • Endothelin receptor blockers
    • VEGF blockers
    • Calcitrol
    • Bisphosphonates
    • Vaccine immunotherapy
  • 16. Endothelin recepetor
    • Endothelin A – Atrasentan
      • Phase 3 trial failed
    • ZD4054
  • 17.  
  • 18.
    • VEGF
      • CALGB 90401-Despite improvement in PFS, measurable disease response and post-therapy PSA decline, the addition of bevacizumab to docetaxel and prednisone did not improve OS in men with mCRPC, and was associated with greater morbidity and mortality
      • Afigerecpt (vegf trap)
    • Calitriol
  • 19.
    • BUT
      • Phase 3 trial was close by data safety monitoring commitee- high number of deaths
  • 20.
    • Bisphosphonates
      • Zolendronic
      • Riseadronate
    • Vaccine immunotherapy
      • Phase 3 trail was closed
    Monotherapy of docetaxol remains std in first line
  • 21. Denosumab
    • Bone metastases from hormone-refractory (castration-resistant) prostate cancer (CRPC) are associated with RANKL-mediated osteoclast activation resulting in bone destruction and skeletal-related events (SRE)
    • Denosumab is a fully human monoclonal antibody against RANKL
    • 120 mg subcut 4 weekly with ca and vit d supp
    • Denosumab demonstrated superiority over ZA in delaying or preventing SREs in patients with bone metastases from CRPC.
    • Adverse events were consistent in both treatment groups with those previously reported in advanced cancer populations.
  • 22. Second line therapy
    • Issues
      • Elderly
      • Frail
      • Tolerability
  • 23.  
  • 24.  
  • 25.  
  • 26.  
  • 27.  
  • 28. Metronomic chemotherapy
    • HRPC who failed at least docetaxel-based chemotherapy were proposed metronomic cyclophosphamide-prednisolone regimen, and were prospectively registered
    • Metronomic cyclophosphamide prednisolone was safe, well tolerated, and demonstrated interesting clinical activity, yielding a
      • prostate specific antigen decrease by ≥50% in 26% of patients
      • decrease by ≥30% in 48% of patients, but also favorable palliative effects on pain in 43% of patients.
      • The median progression-free survival was 6 months (95% CI: 4-8 months) and the median overall survival was 11 months (95% CI: 7-19 months).
  • 29.  
  • 30. Conclusion
    • Use of chemotherapy has increased survival in HRPC
    • The quest for newer and better agents in first and second line is ongiong
    • Use of metronomic in second line needs futher studies
  • 31.  

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